Tag Archives: H5N1

The highly controversial report from Dutch flu researcher Dr. Ron Fouchier on creating a form of H5N1 avian influenza that’s airborne transmissible between mammals finally appeared this afternoon in Science magazine, after months of dickering over whether this paper would get published and what information it would include.

But, with much of the content of both Dr. Fouchier’s paper, as well as a report on a similar study by Dr. Yoshihiro Kawaoka that appeared last month in Nature, already fairly well known and widely discussed, perhaps the biggest news in today’s reports came in some of the related papers published by Science and in an update about the H5N1 research moratorium made during a press conference yesterday.

courtesy Plaskov, Wikimedia Commons

At the height of the mammalian-transmissible H5N1 debate last winter, Dr. Fouchier and Dr. Kawaoka and several other flu researchers declared a voluntary, temporary stop to any further research on the transmissibility or pathogenesis of H5N1. Speaking at a press conference on June 20 organized by Science magazine to discuss today’s package of H5N1 reports and analysis, Dr. Anthony Fauci, director of the National Institutes of Allergy and Infectious Diseases (which funded the transmissible H5N1 work), said, “The reason why you have not heard any announcement about the moratorium is that we are still struggling with the criteria for the next phases of experiments. We are working hard right now to get processes in place where we could have broad general criteria for the kinds of experiments that could be done.” A meeting is scheduled in July in New York that will bring together a worldwide group of influenza researchers and surveillance experts who will try to produce those criteria, Dr. Fauci said. The meeting “will discuss in detail the kinds of approaches we can have to try to expedite as quickly as possible the lifting of the moratorium.”

One of the new studies that accompany the Fouchier paper today is an analysis led by researchers at Cambridge University who used the findings on H5N1 mutations that contribute to mammalian transmissibility to develop a mathematical model to calculate the risk that such viruses could appear in nature. Their conclusion: Current best estimates indicate that the needed panel of mutations could evolve within a single mammalian host, making the possibility of a respiratory-drop transmissible strain of H5N1 virus occurring in nature “a potentially serious threat.” But a more quantifiable estimate of the risk—a specific number—is not yet possible, they said.

“We now know that we are living on a fault line, an active fault line,” when it comes to the potential for H5N1 to become mammalian transmissible in the real world, said Dr. Derek J. Smith, head of the Cambridge group, during yesterday’s press conference. “Now what we need to know is how likely it is.”

Another part of today’s H5N1 package dealt with steps that could be taken right now to speed up influenza vaccine production in response to a newly emerged pandemic strain, something that warrants its own blog post.

If a strain of avian H5N1 influenza that readily spread from person to person were to appear in the real world, the great fear is that it would produce a deadly pandemic to dwarf what happened in 1918.

The best defense against flu pandemics are vaccines, and the most recent experience with a global flu pandemic, in 2009, highlighted the gaps that existed in getting vaccine quickly made in large amounts. Three years ago, despite the U.S. government marshaling all its infectious disease-fighting muscle, the effort wound up delivering most of the vaccine too late to matter. The pandemic peaked in October 2009, while the vaccine supply didn’t hit its stride until sometime in December.

In a report published today in Science as part of its H5N1 flu package, Dr. Rino Rappuoli, head of vaccines research for Novartis, spelled out seven steps that could hasten vaccine production for a newly appearing pandemic flu. The two most novel moves involve having vaccine manufacturers prepare in advance synthetic “vaccine seed” viruses and also adopting new ways to quantify viral antigens, a process that alone took about 2 months in 2009, he said. Adopting these two technological innovations could transform the vaccine-producing process “from a mid-20th century system … into a 21st century system of instantaneous electronic information exchange followed by immediate production.”

The modernized system would mean sequencing a newly isolated pandemic virus in the field and then — instead of shipping the virus — just sending gene sequences, followed by replicating the hemagglutinin gene at a remote site, putting the new gene into a waiting scaffold vaccine virus, and launching vaccine production.

If these two changes had been in place in 2009, “the vaccine would have been available in large quantities before the peak of viral infection,” Dr. Rappuoli said in his paper.

More importantly, speaking at a June 20 press conference Dr. Anthony Fauci said that the National Institutes of Health, as well as the Centers for Disease Control and Prevention and the Food and Drug Administration, had already begun to move on this, adopting “the fundamental principles of bringing influenza vaccinology into the 21st century.” Steps already taken along the lines of what Dr. Rappuoli suggested carry the potential for “a significant change right now” in the time needed to get out a pandemic vaccine, Dr. Fauci said.

He particularly cited NIH studies underway using an immunoadjuvant to expand the coverage potential of stockpiled H5N1 vaccine, a step that would “markedly accelerate availability.

“We are right now in a much better position [to distribute pandemic vaccine quickly] than we were in 2009 when we had vaccine available only after the peak of the H1N1 pandemic,” Dr. Fauci said.

The current U.S. influenza seasonal epidemic, the mildest in years, is in its death throes, based on infection trends over the past several weeks, including the most recent data released on May 11 by the Centers for Disease Control and Prevention.

During the week that ended on May 5, 13.7% of U.S. respiratory surveillance specimens tested positive for influenza, continuing the clear downhill slope of U.S, flu cases since this season’s U.S. epidemic peaked at 30% positive during the week of March 11-17. The CDC hasn’t yet declared the current, 2011-2012 flu-season’s epidemic, which started in late February, officially over—it can’t until the influenza-positive rate falls back below 10%–but the epidemic curve’s steep downward track (see graphic) is as well defined as the far side of L’Alpe d’Huez.

graphic courtesy of the CDC

With the current influenza epidemic nearly ended, the season’s numbers paint a decidedly benign picture. So far, 22 children have died from influenza; if that figure continues to grow as it has so far it will top out as the lowest since the CDC began collecting these data in 2004.

Other markers of how mild the 2011-2012 season has been include the number of U.S. patients hospitalized for influenza, which sits below past seasons, and the proportion of deaths attributable to pneumonia or influenza has hovered below the epidemic threshold for that measure all season.

During a winter and spring where the influenza world focused on mammalian-transmissible H5N1 flu, strains dubbed by some the “doomsday” virus, having such a mild seasonal flu season tossed at us can’t help but be seen as some ironic, natural-world prank. On a purely rationale basis, year-to-year variations in seasonal flu have nothing whatsoever to do with the looming danger from H5N1 flu, but with this infectious-disease juxtaposition I can’t help but imagine that somewhere, off in the distance, I hear a quiet, cosmic chortle.

Just when it seemed like consensus existed on how to handle the hot potato of mammalian-transmissible H5N1 influenza, the public release on Friday afternoon of a letter sent April 12 from the respected influenza and public health researcher Dr. Michael Osterholm to a National Institutes of Health official collapsed the apparent consensus like a house of cards.

To recap: On March 29 and 30, the U.S. government’s National Science Advisory Board for Biosafety (NSABB), organized by the NIH’s Office of Science Policy, met to reconsider the NSABB’s original decision last December that said the paper written by Dr. Yoshihiro Kawaoka and another paper by Dr. Ron Fouchier on their respective efforts to produce and study H5N1 mutants transmissible by air from ferret to ferret should only be published without the methods sections, a way to prevent release of the details on how they developed these potentially dangerous mutant strains. The initial NSABB recommendation to allow publication of only the redacted papers failed to win support from a panel convened by the World Health Organization in February, creating a conflict between the NSABB (and hence the NIH) and the WHO. Claiming that new data first revealed to the WHO group led to the different outcome, Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases — the U.S. agency that sponsored the work of both Dr. Kawaoka and Dr. Fouchier — called on the NSABB to rethink its initial decision, which resulted in the NSABB reversing itself on March 30 and supporting full publication, in a unanimous vote for Dr. Kawaoka’s work, and in a 12-6 vote for Dr. Fouchier’s. So, by early April, the NSABB (and hence, pending official U.S. policy) and the WHO agreed that full H5N1 publication could proceed. Peace reigned across the land.

Dr. Michael Osterholm

Until 2 weeks later, when Dr. Osterholm an NSABB member, upset the tranquility by writing his bombshell letter to Dr. Amy Patterson, NIH’s associate director for Science Policy. In it, Dr. Osterholm took vigorous swipes at how the NIH set up the NSABB’s reconsideration session and detailed his grave concerns about public release of how the H5N1 work was done. Both “Science” and “Nature” received the letter on April 13, and according to a report in “Nature,” Dr. Osterholm said he was not the source for the leak.

“I believe the agenda and speakers for the March 29 and 30 NSABB meeting as determined by the Office of Biotechnology Activities [part of the NIH’s Office of Science Policy] staff and other U.S. government officials was designed to produce the outcome that occurred,” Dr. Osterholm charged in his letter. “It represented a very ‘one-sided’ picture of the risk-benefit of the dissemination of the information in these manuscripts. The agenda was not designed to promote a balanced reconsideration of the manuscripts.”

A major problem, he said, was that the “experts that addressed [the March NSABB session] have a real conflict of interest in that their laboratories are involved in this same type of work and the results of our deliberations directly affect them too.” The same problem occurred at the WHO meeting in February, he added.

Dr. Osterholm tempered his charge by saying he did not “suggest that there was a sinister motive by the U.S. government,” but still leveled a hefty blast, saying “I believe there was a bias toward finding a solution that was a lot less about robust science- and policy-based risk-benefit and more about how to get us out of this difficult situation.”

The upshot was that in the revised decision NSABB, U.S. policy makers, and researchers failed to “come to grips with the very difficult task of managing dual-use research of concern and the dissemination of potentially harmful information to those who might intentionally or unintentionally use that information in a harmful way.” His worry is — if not in this case — “will the Board ever find a bright line for redacting publication” of any future research that could potentially threaten public health?

Dr. Osterholm cited a major danger if details of this research became fully public: “A ferret-to-ferret experiment is expensive and technically demanding, and could only be done by a handful of labs in the world. Once the mutations are public, individuals … in many other labs could generate the mutants in a few weeks given several thousand dollars for gene synthesis,” using reverse genetics.

Finally, Dr. Osterholm questioned the public-health benefit from full release of the methods sections of the two H5N1 papers. “The most important aspect of the results in these two studies on surveillance and control has already been accomplished namely alerting the world to the possibility that H5N1 influenza virus surely can become a mammalian-transmitted virus and poses real pandemic potential.” Publication of more details from the research will not add to that alert, nor would it immediately help in the development or production of countermeasures against a potential H5N1 pandemic, he said.

Despite his concerns over full disclosure of the methods, Dr. Osterholm affirmed his overall support for this H5N1 research in a comment to “Nature” on Friday. “I have been and continue to be a supporter of this kind of research,” he told the journal.

The biologic properties that allowed mutated strains of avian H5N1 virus to pass between ferrets in a model of mammalian transmission all share certain, apparently critical biologic traits, Dr. Ron Fouchier said at an open meeting on H5N1 research held today and on April 4 in London.

“There is clearly a pattern of what biologic traits a virus needs to get” to allow mammalian transmission, an important clue to what to look for in naturally-occurring H5N1 mutations, said Dr. Fouchier, a researcher at Erasmus Medical Center in Rotterdam and head of one of the two groups that generated the controversial research papers that may now soon be published.

Along with the American Society for Microbiology, the UK’s Royal Society sponsored the two-day session that provided the most thorough information yet available on the H5N1 research done by Dr. Fouchier, and separately by Dr. Yoshihiro Kawaoka at the University of Wisconsin in Madison, as well as comments on the appropriateness of the research and its publication by several other speakers.

Dr. Kawaoka/image by Mitchel Zoler

Dr. Kawaoka described how he focused on the impact of mutations in the H5 hemagglutinin protein in viruses that combined the mutated gene with other genes from the 2009 pandemic H1N1 strain. He concluded from his work so far that “we need to enhance surveillance and the capacity to analyze H5N1 viruses and continue to identify mutations that would convert H5N1 viruses to those transmissible in mammals.” He also noted the “striking similarity” in findings between his work and that of Dr. Fouchier, even though they used different approaches for generating mammalian-transmissible forms of H5N1 (but both used ferret-model systems). Dr. Kawaoka also downplayed drawing a distinction between the mutations he generated and studied in his experiments and what might occur in the real world. “The risk is out there in nature” for the potential formation of H5N1 that is transmissible between mammals through the air. The four mutations he found that made airborne transmission possible between ferrets “is nothing” for a highly mutable virus like influenza.

Dr. Fouchier agreed. So far, spread of H5N1 virus from birds to mammals has been studied for 15 years. Air-borne spread of H5N1 between mammals will “eventually” happen he said; all it will take will be the passage of time, chance, and selection.

Dr. Fouchier/image by Mitchel Zoler

Dr. Fouchier noted that his experiments differed from Dr. Kawaoaka’s by not involving a reassortment step and dealing exclusively with the avian H5N1 virus. He said he was satisfied that the transmissible model strain he now has, which is not very efficiently passed between animals nor very pathogenic, was sufficient to move on to the next studies he wants to do: Look at the biologic traits of the transmissible virus and identify a set of key biologic properties that can be used for surveillance of naturally-occurring mutant strains; determine whether all H5N1 viral lineages have the potential to become transmissible between mammals; and determine whether any vaccine types seem best for pandemic preparedness.

Also speaking at today’s session was Dr. Thomas Inglesby, director of the Center for Biosecurity of the University of Pittsburgh, who reiterated his prior opinion that creating and studying engineered H5N1 mutants posed too big a health risk to proceed. He said that similar, valuable information could be obtained by studying naturally-occurring H5N1 mutations.

In his presentation, Dr. Paul Keim, acting chairman of the U.S. National Science Advisory Board for Biosecurity (NSABB), cited four reasons why the NSABB voted last week to recommend full publication of both Dr. Kawaoka’s and Dr. Fouchier’s papers on their research, reversing the position the Board first took last October. The revised versions of both articles that the NSABB examined last week had better clarity on the balance of risk and benefit from the research, and the Board also received additional, non-public information on benefits and risks, he said. The NSABB also drew on a new policy announced last week that set an official U.S. position on dual-use research, and the NSABB was also swayed by the lack of a mechanism for distributing restricted parts of the reports to approved recipients.

Late this afternoon, the U.S. National Science Advisory Board for Biosecurity announcedthat it reversed its initial ruling, and will support open publication of two research articles that describe the creation of mutant strains of H5N1 avian influenza that are capable of air-borne transmission between mammals.

The new NSABB decision, which came at the end of two days of consideration of revised versions of both papers, brought the U.S. panel into agreement with a review panel convened by the World Health Organization in February that also supported full publication of the papers.

H5N1 virus/courtesy CDC; Cynthia Goldsmith, Jackie Katz

When the NSABB first reviewed the original versions of the papers last December, it decided that publication of the methods sections of the article written by Dr. Yoshihiro Kawaoka of the University of Wisconsin in Madison, and a second article written by Dr. Ron Fouchier of Erasmus Medical Center in Rotterdam, posed too much of a public health risk because of the “dual use” risk of their work. The NSABB said it feared that full disclosure of details of how these researchers produced the mutated H5N1 strains that allowed the highly pathogenic virus to spread through the air from mammal-to-mammal (in a ferret model) posed too great a danger that the information could be used in a way that endangered public health.

In its statement today, the NSABB said that “While the communication of the information in these revised manuscripts still presents dual use concerns, the additional information changed the Board’s risk/benefit calculation.”

The NSABB said that it voted unanimously to recommend full publication of Dr. Kawaoka’s revised manuscript, and that it voted 12-6 in favor of full publication of Dr. Fouchier’s revised manuscript.

“The data described in the revised manuscripts do not appear to provide information that would immediately enable misuse of the research in ways that would endanger public health or national security,” the NSABB said.

Although the NSABB statement did not elaborate on the nature of the revisions, Dr. Fouchier said at an open meeting in February that the mutant influenza he had produced was not as easily transmitted nor as pathogenic as initial press reports had suggested. Speaking at that meeting, Dr. Anthony Fauci , director of the National Institute of Allergy and Infectious Diseases, said that this revised information from Dr. Fouchier had led to the WHO’s decision, and prompted him to ask the NSABB to reconsider both manuscripts.

Dr. Ron Fouchier, one of the two researchers who developed and studied mutant forms of avian H5N1 influenza that’s transmissible through the air, provided new details of his findings at a conference this morning in Washington. He explained that the mutant virus is not nearly as deadly or transmissible as many people have supposed.

This new information seems to be, at least in part, at the root of the different conclusions recently reached by the U.S. National Science Advisory Board for Biosecurity (NSABB) and by a group organized by the World Health Organization (WHO) on whether detailed methods of the H5N1 mutant research should be released to the public. During the past few days, the National Institutes of Health called on the NSABB to meet again to hear the new data and see if it would change the Board’s decision to keep the methods sections of the papers under wraps, Dr. Anthony Fauci said at today’s meeting.

ferret; courtesy hemmer@fr.wikipedia, Wikimedia Commons

“This virus does not kill ferrets that are sneezed on [by ferrets already infected with mutant H5N1], and if it was released it is unlikely that it would spread like wildfire, and to extrapolate that it would spread like wildfire in humans is really farfetched at this stage,” said Dr. Fouchier, a researcher at Erasmus University in Rotterdam. “This virus does not spread like a pandemic or seasonal influenza virus,” he said in a session that dealt with H5N1 issues during a meeting on Biodefense and Emerging Diseases sponsored by the American Society for Microbiology. He called any notion that the mutant avian H5N1 flu he created could transmit readily in aerosolized form from ferret-to-ferret a “misperception.”

In addition, many people have had a second important misperception of the virus he’s studied: The H5N1 mutant strains he created are not highly lethal.

“It’s very clear that H5N1 is highly lethal in chickens, but in mammals that’s not the case.” The mutant form of the virus will kill a ferret if you place a large dose of the virus—a million virions—directly into the animals lower respiratory tract. That kills the animal in about 3 days, he said. But if a more modest and typical inoculum gets introduced intranasally to a ferret, the animal simply gets a flu-like illness but recovers. “We saw no severe disease in any of the seven animals that received virus by aerosol,” he said.

A third, heartening observation he’s made about how mammalian-transmissible H5N1 behaves is that ferrets exposed to seasonal flu before exposure to the H5N1 mutant “are fully protected against severe disease.” His conclusion from this: “It’s unlikely that humans have no cross protection to H5N1, so very few would develop severe disease. Most [people] would be protected by cross-protective immunity.”

According to Dr. Fauci, director of the National Institute of Allergy and Infectious Disease, these clarifications from Dr. Fouchier first came to light earlier this month during a meeting on H5N1 convened by the WHO in Geneva. These new data, as well as the recommendations made by the WHO group, led Dr. Fauci to ask the NSABB to reconvene.

“The NIH continues to support the NSABB recommendations regarding the original manuscripts [to publish redacted versions of the papers], and supports revision of the manuscripts to include new data and explicit clarifications of old data,” Dr. Fauci said. “There was obviously a disagreement in the recommendations between Geneva and the NSABB. There was a strong feeling to reconvene the NSABB to give them the benefit of the same information and discussion as in Geneva.”